Phenotype, Progression and Immune Correlates of Post-Tuberculosis Lung Disease

结核病后肺病的表型、进展和免疫相关性

• 批准号: 10250311
• 负责人: Akshay Nitin Gupte
• 金额: $ 13.54万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10250311
• 关键词: Acute Lung Injury; Address; Adult; Affect; Air Movements; Award; Bronchodilator Agents; Cessation of life; Chronic; Chronic Obstructive Airway Disease; Chronic lung disease; Clinical Research; Complement; Complex; Cross-Sectional Studies; Data; Data Reporting; Diagnostic; Disease; Disease Progression; Evaluation; Forced expiratory volume function; Future; High Prevalence; Image; Immune; Immune Targeting; Immunologic Markers; Immunologics; Impairment; India; Infectious Disease Epidemiology; Infectious Diseases Research; Inflammation; Inflammatory; Intervention; Knowledge; Link; Lung; Lung Inflammation; Lung diseases; Measurement; Measures; Mentorship; Microbiology; Monitor; Morbidity - disease rate; Morphology; Natural History; Outcome; Oxidative Stress; Participant; Pathway interactions; Patients; Pattern; Phase; Phenotype; Plasma; Play; Preventive; Process; Prognosis; Prospective cohort study; Pulmonary Function Test/Forced Expiratory Volume 1; Pulmonary Tuberculosis; Pulmonary function tests; Relapse; Reporting; Research; Research Personnel; Risk Factors; Role; Secondary to; Severities; Site; Smoking; Smoking Status; Spirometry; Sputum; Statistical Methods; Structure of parenchyma of lung; Testing; Therapeutic; Therapeutic Trials; Tissues; Training; Tuberculosis; Vital capacity; Work; X-Ray Computed Tomography; airway obstruction; clinically relevant; cohort; cytokine; detector; follow-up; functional outcomes; imaging study; immune activation; immunoregulation; inflammatory marker; lung imaging; lung injury; mortality; never smoking; novel; prevent; prognostic; prospective; pulmonary function; pulmonary function decline; recruit; smoking exposure; targeted treatment; tuberculosis treatment; young adult

PROJECT ABSTRACT Pulmonary tuberculosis (PTB) is associated with lung injury which can persist despite successful therapy. Lung sequelae of treated PTB are increasingly recognized as an independent risk factor for chronic obstructive pulmonary disease (COPD) and, an important contributor of excess morbidity and mortality. Our prior work measuring lung function in a cohort of young and predominantly never-smoking adults with PTB who successfully completed TB therapy found 14% had COPD, an additional 10% had airflow obstruction which responded to bronchodilator therapy, and nearly 50% had a restrictive spirometry pattern. These data suggest that the predominant phenotype of post-PTB chronic lung disease (CLD) may differ from that seen in smoking-associated COPD. Post-PTB CLD may have distinct natural history, prognosis and therapeutic strategies which, till date, have not been investigated. Our prior work also found that post-PTB CLD was associated with the duration of illness prior to initiating TB therapy and high levels of slow-to-resolve pro-fibrotic cytokines during late TB therapy. Together, these data suggest that the vast majority of acute lung injury associated with PTB likely occurs prior to and shortly after initiating TB therapy, and that elevated or persistent levels of key immune markers may be detrimental through their impact on lung tissue remodeling. However, few studies have prospectively characterized immune markers associated with long-term functional outcomes in PTB. This is an important knowledge gap preventing the identification of potentially modifiable immune pathways for targeted host-directed therapies, and the optimal timing of intervention with these therapies, to prevent post-PTB CLD. To address these knowledge gaps, we will nest a prospective cohort study within the RePORT-India TB Research Consortium to 1) characterize the early natural history of post-PTB CLD and provide rationale for long-term monitoring and bronchodilator therapy in affected cases, 2) characterize the functional and morphological phenotype of post-PTB CLD by serial pulmonary function testing and multi-detector computed tomography, 3) identify immune profiles measured during early, late and post-therapy associated with post-PTB CLD. Through this K99/R00 award, Dr. Gupte will complement his prior training in infectious disease epidemiology by obtaining mentorship in the identification, measurement and interpretation of 1) clinically relevant lung function and imaging outcomes for CLD research; 2) potentially modifiable immune markers of chronic lung injury for future therapeutic trials; and 3) advanced statistical methods for the integrated analysis of lung function, imaging and immunological data. This K99/R00 award will help Dr. Gupte develop into an independent investigator conducting impactful clinical research at the intersection of infectious and chronic lung diseases globally, while also building site capacity and generating novel data to support subsequent R01 applications aimed at identifying diagnostic, prognostic and therapeutic strategies for CLD in treated PTB.

项目摘要 肺结核（PTB）与肺损伤有关，即使治疗成功，肺损伤也会持续存在。肺 PTB治疗的后遗症越来越被认为是慢性阻塞性肺疾病的独立危险因素， 肺疾病（COPD），并且是过度发病率和死亡率的重要贡献者。我们以前的工作 测量一组年轻且主要从不吸烟的PTB成年人的肺功能， 完成TB治疗后，发现14%患有COPD，另外10%患有气流阻塞， 支气管扩张剂治疗，近50%有限制性肺功能模式。这些数据表明 PTB后慢性肺疾病（CLD）的主要表型可能与吸烟相关的 慢性阻塞性肺病PTB后CLD可能具有不同的自然病史、预后和治疗策略，迄今为止， 还没有被调查。我们先前的工作也发现PTB后CLD与PTB持续时间有关。 在开始TB治疗之前的疾病和在晚期TB治疗期间的高水平的缓慢消退的促纤维化细胞因子。 总之，这些数据表明，绝大多数与PTB相关的急性肺损伤可能发生在 在开始结核病治疗前和治疗后不久，关键免疫标志物水平的升高或持续， 通过它们对肺组织重塑的影响而有害。然而，很少有研究预测 与PTB长期功能结局相关的特征性免疫标志物。这是一个重要 知识差距阻碍了对靶向宿主定向免疫的潜在可修饰免疫途径的识别 治疗，以及这些治疗干预的最佳时机，以预防PTB后CLD。解决 鉴于这些知识差距，我们将在印度结核病研究报告中嵌套一项前瞻性队列研究 联合会：1）描述PTB后CLD的早期自然史，并提供长期治疗的依据 监测和支气管扩张剂治疗，2）表征功能和形态 通过系列肺功能测试和多探测器计算机断层扫描确定PTB后CLD的表型，3） 鉴定在与PTB后CLD相关的早期、晚期和治疗后期间测量的免疫谱。通过 在K99/R 00奖中，Gupte博士将通过获得 指导识别、测量和解释1）临床相关肺功能和成像 CLD研究的结果; 2）慢性肺损伤的潜在可修饰免疫标志物，用于未来的治疗 先进的统计学方法，用于肺功能、影像学和免疫学的综合分析 数据这个K99/R 00奖项将帮助Gupte博士发展成为一名独立的研究人员， 全球传染病和慢性肺部疾病交叉点的临床研究，同时也是 能力和生成新数据，以支持后续R 01应用， 治疗PTB中CLD的预后和治疗策略。